| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Dipartimento Clinico-Sperimentale di Medicina e Farmacologia-Sezione di Endocrinologia (F.V., V.P.L.P., M.M., G.S., M.G.C., F.M., M.A.V., F.T.), Dipartimento di Scienze Pediatriche-Sezione di Neuropsichiatria Infantile (M.S., G.T., A.C.), and Dipartimento di Diagnostica di Laboratorio-Servizio di Biochimica Clinica (A.A.), University of Messina, Messina 98125, Italy
Address all correspondence and requests for reprints to: Prof. Francesco Vermiglio, M.D., Cattedra di Endocrinologia, Policlinico Universitario, Via Consolare Valeria 98125 Messina, Italy. E-mail: francesco.vermiglio{at}unime.it.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Attention deficit and hyperactivity disorder (ADHD) was diagnosed in 11 of 16 area A children (68.7%) but in none from area B. Total intelligence quotient score was lower in area A than in area B children (92.1 ± 7.8 vs. 110 ± 10) and in ADHD children when compared with both non-ADHD children from the same area and control children (88.0 ± 6.9 vs. 99.0 ± 2.0 and 110 ± 10, respectively). Seven of 11 ADHD children (63.6%) were born to the seven of eight area A mothers who became hypothyroxinemic at early gestation, whereas only one of five non-ADHD children was born to a woman who was hypothyroxinemic at 20 wk of gestation.
So far, a similar prevalence of ADHD has been reported only in children with generalized resistance to thyroid hormones. This might suggest a common ADHD pathogenetic mechanism consisting either of reduced sensitivity of the nuclear receptors to thyroid hormone (generalized resistance to thyroid hormones) or reduced availability of intracellular T3 for nuclear receptor binding. The latter would be the ultimate consequence of maternal hypothyroxinemia (due to iodine deficiency), resulting in a critical reduction of the source of the intracellular T3 available to the developing fetal brain.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The present long-term prospective study was carried out on the offspring of a series of women, all born and living in the same moderately ID area, whose thyroid function was studied during early pregnancy with the aim of identifying the long-term effects of ID-related maternal hypothyroxinemia on the behavioral, psychoneurological, and intellectual development of children.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The study group included 16 children born to 16 healthy mothers living in the moderately ID and extensively studied area (area A) and 11 control children born to 11 age-matched women from an area with marginally sufficient iodine intake (area B).
Table 1
shows the characteristics of both areas when the children were conceived (1990–1992) and at the present time.
|
To rule out other psychiatric or primary disorders that would more adequately explain the clinical picture of ADHD, we combined staff from the departments of endocrinology, neurology, developmental pediatrics, and psychology (5). The first behavioral and neuropsychological evaluation (1994) was performed on a clinical observation basis when the children were 18–36 months old by two independent examiners (M.S. and G.T.), who were unaware of their mothers’ thyroid function during pregnancy. All children from both areas A and B were subsequently reevaluated (2001–2002), by the same examiners, when they were 8–10 yr old. Besides neurological examination and ADHD screening, the second evaluation included intelligence testing to rule out mental retardation, in which inattention and hyperactivity symptoms are commonly found.
Neurological evaluation, carried out according to the directions of Touwen (6) when the children were 18–36 months and 8–10 yr old, included assessment of the child while sitting, standing, walking, and lying, as well as examination of muscle tone, reflexes, and general data (dominance, fine motor coordination, sensory examination, speech, and language).
Screening for ADHD
The reference scale for inattention and hyperactivity derives from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition-Text Revision (DSM-IV-TR) (7), validated by subscales for the Italian population (8). The essential feature of ADHD is a persistent pattern of inattention and/or hyperactivity-impulsivity. Analysis of the structured psychiatric interviews makes it possible to identify different subtypes of the disorder, depending on the prevalence (and persistence for at least 6 months) of different symptoms (nine for the attention deficit variant and nine for the hyperactive variant): 1) ADHD, combined type subtype (6 of 9 or more inattention symptoms and six of nine or more hyperactivity/impulsivity symptoms); 2) ADHD, predominantly inattentive type subtype (six of nine or more inattention symptoms but fewer than six of nine hyperactivity/impulsivity symptoms); 3) ADHD, predominantly hyperactive-impulsive type subtype (six of nine or more hyperactivity-impulsivity symptoms but fewer than six of nine inattention symptoms). The minimum score for a child to be considered to be affected with ADHD was, therefore: six of nine for both ADHD predominantly inattentive type, and ADHD predominantly hyperactive-impulsive type subtypes; and at least 12 of 18 for the ADHD combined type subtype.
The questionnaires with the items listed in the DSM-IV-TR were distributed both to parents and to teachers when the children’s ages ranged between 8 and 10 yr, with directions to mark each item "often", "sometimes", "rarely", or "never". An item was considered positive when both parents and teachers marked it "often".
Intelligence testing
Intelligence was measured by the most widely used intelligence test, the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III) (9), which provides a full-scale intelligence quotient (IQ) score and subscale scores (range, 40–160) for verbal skills and performances in the following areas: general information, general comprehension, arithmetic, similarities, vocabulary, digit span, picture completion, picture arrangement, block design, object assembly, coding, and mazes.
The WISC-III full-scale IQ score comprises three subscores devoted to items considered free from distractibility (arithmetic, digit span, and coding—WISC-III freedom-from-distractibility score); to verbal items (general information and comprehension, arithmetic, similarities, vocabulary, and digit span—WISC-III verbal IQ score) and to performance items (picture completion and arrangement, block design, object assembly, coding, and mazes—WISC-III performance IQ score).
According to this scale, a child is considered to be mentally retarded when his total IQ (t-IQ) score is less than 75 points (10).
Children’s thyroid function tests
All children were euthyroid at delivery, as proved by the results of neonatal screening for congenital hypothyroidism. Serum free T3 (FT3), free T4 (FT4), and TSH were measured in all children when they were 18–36 months old (January-June 1994) using the same commercial kits as used to study their mothers (see below) and at 8–10 yr (November 2001-May 2002) using commercial kits supplied by Diagnostic Products Corporation, Los Angeles, CA (Immulite 2000 Analyzer).
Maternal thyroid function tests
We measured serum T3, T4, FT3, FT4, TSH, and T4-binding globulin (TBG) values at three different points in time (between 5 and 10, 11 and 14, and18 and 20 wk of gestation). These correspond approximately to times before (8–13 wk) and subsequent to (20 wk) the onset of secretion of thyroid hormones by the fetal thyroid and will be referred to as 8, 13, and 20 wk of pregnancy, respectively. TBG saturation by T4 was calculated as the molar T4/TBG ratio, assuming 57 kDa to be the molar mass for TBG.
Maternal circulating total T4 and T3 (RIA), TSH (immunoradiometric assay), FT3 and FT4 (Amerlex-MAB, a one-step radiolabeled analog RIA) were determined (1990–1994) using commercial kits supplied by Kodak Clinical Diagnostic Ltd., Amersham, UK. Precision profiles showed inter- and intraassay coefficients of variation not exceeding 5%, over the entire measurement range, for both free thyroid hormones.
Serum antithyroid antibodies were measured using a two-step immunoenzymometric assay supplied by Tosoh Corporation, Tokyo, Japan (AIA-PACK TgAb and TPOAb). TBG concentration was measured using a commercial RIA kit (Behring, Marburg, Germany).
Definition of hypothyroxinemia
The term hypothyroxinemic is used here and elsewhere to indicate pregnant women with normal TSH concentrations (0.4–4.0 µU/ml) but low serum FT4 values as compared with the range values calculated (mean ± 2 SD) at the same stage of pregnancy (8, 13, and 20 wk) in a series of 50 healthy women with moderately adequate iodine intake (150–200 µg iodine/d). Accordingly, normal values at 8 wk were: 1.02–1.72 ng/dl; mean ± SD, 1.36 ± 0.17; median, 1.39 (13.1–22.2 pmol/liter; mean ±SD, 17.6 ± 2.25; median, 17.9). Normal values at 13 wk were: 0.98–1.49 ng/dl; mean ± SD, 1.24 ± 0.12; median, 1.25 (12.7–19.2 pmol/liter; mean ± SD, 16.0 ± 1.64; median, 16.2). At 20 wk, values were: 0.85–1.39 ng/dl; mean ± SD, 1.12 ± 0.13; median, 1.11 (11.0–17.9 pmol/liter; mean ± SD, 14.5 ± 1.7; median, 14.3).
Statistical analysis
Unless otherwise indicated, data are expressed as mean ± SD. Statistical analysis was performed by two-way ANOVA, linear regression, Student’s t test for unpaired data, and the 
2 test.
Informed written consent was obtained from all the mothers recruited and from both the children’s parents.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
All the children from both areas were euthyroid at neonatal screening and afterward (18–36 months and 8–10 yr) (data not shown). At clinical neuromotor evaluation, no child showed any neurological signs typically belonging to the spectrum of ID disorders (11).
ADHD testing
In nine of 16 children from area A, clinical observation in 1994 had revealed the presence of psychoneurological features suggestive of ADHD. This diagnosis was confirmed in 2001–2002 (DSM-IV-TR) in all of them and in a further two area A children in whom ADHD had not been suspected in 1994. None of the 11 area B children were affected with ADHD, because the tentative diagnosis made in 1994 for one of them was not confirmed in 2001–2002.
Therefore, ADHD affected 11 of 16 (68.7%) children from area A (5 of 11 ADHD, combined type subtype; five of 11 ADHD, predominantly hyperactive-impulsive type subtype; and one of 11 ADHD, predominantly inattentive type subtype).
To improve the readability of the further results, the area A children and (their respective) mothers will henceforth be referred to as ADHD+ve and ADHD–ve area A subgroups, according to the presence or absence of ADHD, respectively.
Intelligence testing
Full-scale IQ score and subscale scores for each item are summarized in Table 2.
|
Mean t-IQ score was lower in area A than in area B children by approximately 18 points (92.1 ± 7.8 vs. 110 ± 10, P < 0.00005).
When we compared the intelligence test results of the ADHD+ve, ADHD–ve, and control children (Table 2
), we observed that t-IQ score was lower in ADHD+ve than in ADHD–ve children by 11 points; and in both subgroups, it was lower than in the control group by 22 and 11 points, respectively. The attention WISC-III freedom-from-distractibility subscore was lower only in ADHD+ve children than in the controls, whereas the WISC-III verbal IQ subscore was lower in ADHD+ve than in either ADHD–ve or control children (14.4 and 21.4 points, respectively). The WISC-III performance IQ subscore was lower in both ADHD+ve children and ADHD–ve children than in controls by 19.3 and 12.5 points, respectively.
Of the ADHD+ve children, three of 10 had a t-IQ score 
90, six of 10 ranged between 90 and 75, and only one of 10 had a score less than 75. Both the ADHD–ve and the control children had a t-IQ score more than 90.
Maternal thyroid function and psychoneurological impairment
For the purposes of our study, we compared the changes in maternal thyroid function of both ADHD+ve (n = 11) and ADHD–ve (n = 5) area A subgroups with those of the control area mothers (n = 11) over the first half of gestation.
Average values of maternal T3, T4, FT3, FT4, TSH, and TBG saturation by T4 at 8, 13, and 20 wk of gestation, in both area A ADHD+ve and ADHD–ve subgroups and in area B control mothers, are illustrated in Fig. 1.
|
Figure 2 shows individual maternal FT4 and TSH data for both area A and area B subgroups. Of the 16 area A women, eight had serum FT4 values that were lower than normal for the gestational week. In fact, hypothyroxinemia occurred at 8 wk in one ADHD+ve mother, at 13 wk in two other ADHD+ve mothers, and at 20 wk in one ADHD–ve and in four more ADHD+ve mothers. In two of these eight women, hypothyroxinemia was accompanied by a slight increase in TSH concentration, one from the second sampling on and the other at 20 wk. In the mothers from area B, both FT4 and TSH values were consistently found to fall within the normal range in all but one woman, who was found (at the 13th wk of gestation) to be transiently hypothyroxinemic.
|
Seven of eight (87.5%) women who experienced hypothyroxinemia during early gestation generated seven of the 11 ADHD+ve children, whereas the remaining four of 11 were born to mothers who remained euthyroid throughout the first half of their pregnancies. Conversely, of the five ADHD–ve children, four (80%) were born to mothers who had remained euthyroid throughout the study period, whereas only one was born to a hypothyroxinemic mother.
Finally, of the 11 of 16 area A children with neuropsychological disorders, seven of 11 (63.6%) were born to the eight iodine-deficient women who had become hypothyroxinemic during early gestation. As a consequence, the overall prevalence of ADHD among the area A children studied was significantly higher (2, 2.34; P = 0.001) in children born to mothers whose FT4 concentration was below the reference range at midgestation.
Similarly, the children’s t-IQ score was directly (r = 0.56, P < 0.005) related to maternal FT4 and inversely (r =0.63, P < 0.001) related to maternal TSH values at midgestation, when both area A and B were considered as a whole (Fig. 3).
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A high prevalence (70%) of ADHD has been reported in children with GRTH (4), a disease caused by mutations in the thyroid receptor-ß gene and characterized by reduced responsiveness of peripheral and pituitary tissues to the actions of the thyroid hormone.
The present study was based on long-term observation of the neuropsychological and intelligence performances of children born to mothers from a mild-moderate ID area, some of whom developed hypothyroxinemia during early pregnancy. At the time of initial neurological observation, we reported clinical findings that were consistent with a diagnosis of ADHD, but we were not able to confirm this suspicion because the children studied were thought to be still too young (18–36 months). It was for this reason that we prolonged our observation until the children were 8–10 yr old, when conclusive diagnosis of ADHD was made in 11 of 16 (68.7%) children born to mothers from this mild-moderate ID area in whom the disorder was associated with some degree of intelligence failure. In fact, ADHD+ve children’s mean IQ scores (although 75 points in all but one) were 12 and 23 points lower than those of the ADHD–ve and control children, respectively.
When neurological results were related to early-pregnancy maternal thyroid function, it was seen that all 11 ADHD+ve children were born to ID area mothers whose thyroid function proved more heavily compromised than that of the five ADHD–ve mothers and that seven of eight (87.5%) ID area mothers who experienced thyroid failure generated ADHD+ve children. It is worth noting, however, that individual TSH levels fell consistently within the normal range in all but two of these women, whose TSH concentration slightly increased toward the end of the study period. Therefore, most of the ADHD+ve children (seven of 11) were born to mothers who had become hypothyroxinemic during early gestation, whereas four of five (80%) ADHD–ve children were born to mothers who remained consistently euthyroid during the first half of gestation.
The ADHD prevalence of almost 70% in our ID area (rising to 87.5% in hypothyroxinemic mothers), so surprisingly similar to that reported in children with GRTH, seems to point to a strong association of this neuropsychological disorder with both the GRTH syndrome and the ID-induced early gestation maternal hypothyroxinemia. ADHD syndrome associated with GRTH could be the result of the developing brain being deprived of the biological effect of the thyroid hormone, whereas ADHD in children from our ID area could be due to an inadequate supply of maternal thyroid hormone to the fetal brain, development of which therefore suffered from varying (and subtle) degrees of maternal thyroid failure during the first phases of organogenesis.
The role of T4 transfer in human beings in early pregnancy is key to ensuring the normal neurological development of the fetus, which is particularly important before the onset of thyroid hormone secretion by the fetal thyroid (15) (20th wk). The existence of T4 transfer from mother to fetus has been demonstrated by several conclusive studies in both rats (16, 17, 18, 19, 20, 21) and human beings (22). First-trimester fetal tissues are exposed to concentrations of FT4, which have recently been demonstrated in human fetuses to ultimately depend on the circulating maternal levels of T4 or FT4 (23).
The relationship between maternal thyroid hormone deficiency and neurological damage in offspring has already been established by several epidemiological studies in areas with severe ID (24) or normal dietary iodine intake (25, 26) and in animal models (27, 28). Maternal hypothyroxinemia, also observed in areas with adequate iodine intake, has been regarded, so far, as a normal condition, even though reduced intellectual performances have been reported in children born to iodine-sufficient hypothyroxinemic mothers (29). The growing concern that hypothyroxinemia during early gestation could be harmful to the fetus (30, 31, 32) has recently been reinforced by the first experimental evidence of a permanent alteration of cortical cytoarchitecture in the progeny of ID-induced hypothyroxinemic dams (33).
In conclusion and for the first time in a mild-moderate ID area, our data seem to vindicate the hypothesis of a direct causal relationship between ID-induced early gestational maternal hypothyroxinemia and ADHD, which might therefore be considered as a new ID disorder to be systematically screened in the progeny. A recent report indicating that neuropsychological development does not seem to be adversely affected in children whose maternal hypothyroxinemia is corrected within the 24th wk of pregnancy (34) is a strong indication of the need for routine screening and monitoring of thyroid function in early pregnancy. An inadequate dietary supply of iodine, still a widespread problem all over the world (including European countries and the United States) (32), further emphasizes the need for intensive programs of iodine prophylaxis to promptly prevent/correct gestational hypothyroxinemia and the resulting permanent and invalidating neurological damage to progeny.
|
Footnotes |
|---|
Received March 25, 2004.
Accepted August 31, 2004.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  T. Asua, A. Bilbao, M. A. Gorriti, J. A. Lopez-Moreno, M. del Mar Alvarez, M. Navarro, F. Rodriguez de Fonseca, A. Perez-Castillo, and A. Santos Implication of the Endocannabinoid System in the Locomotor Hyperactivity Associated with Congenital Hypothyroidism Endocrinology, May 1, 2008; 149(5): 2657 - 2666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Subsection Reports J. Clin. Endocrinol. Metab., August 1, 2007; 92(8_suppl): s8 - s47. [Full Text] [PDF]
|
|
|
|
|
|
M. Abalovich, N. Amino, L. A. Barbour, R. H. Cobin, L. J. De Groot, D. Glinoer, S. J. Mandel, and A. Stagnaro-Green Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline J. Clin. Endocrinol. Metab., August 1, 2007; 92(8_suppl): s1 - s47. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. De Groef, B. R Decallonne, S. Van der Geyten, V. M Darras, and R. Bouillon Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Eur. J. Endocrinol., July 1, 2006; 155(1): 17 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. Pedraza, M.-J. Obregon, H. F. Escobar-Morreale, F. Escobar del Rey, and G. M. de Escobar Mechanisms of Adaptation to Iodine Deficiency in Rats: Thyroid Status Is Tissue Specific. Its Relevance for Man Endocrinology, May 1, 2006; 147(5): 2098 - 2108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Roberts, M. Srinivas, D. Forrest, G. Morreale de Escobar, and T. A. Reh Making the gradient: Thyroid hormone regulates cone opsin expression in the developing mouse retina PNAS, April 18, 2006; 103(16): 6218 - 6223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Kooistra, S. Crawford, A. L. van Baar, E. P. Brouwers, and V. J. Pop Neonatal Effects of Maternal Hypothyroxinemia During Early Pregnancy Pediatrics, January 1, 2006; 117(1): 161 - 167. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
